Endosseous implant

ABSTRACT

Endosseous implant to be applied to human or animal bone, said implant having a surface made from a selected metal or a selected metal alloy or a ceramic, whereby said metal resp. metal alloy is selected from chromium, niobium, tantalum, vanadium, zirconium, aluminium, cobalt, nickel, stainless steels or an alloy thereof, said surface having a smooth or rough texture, characterized in that said surface has been treated with at least one pharmaceutically acceptable organic compound carrying at least one phosphonic acid group or a derivative thereof preferably a pharmaceutically acceptable salt or ester or amid thereof and method for producing said implant.

The present invention relates to a selected metallic or selected ceramicendosseous implant to be applied to a human or animal bone, said implanthaving a smooth or rough surface texture, and wherein said surface hasbeen treated with at least one selected organic compound carrying atleast one phosphonic acid group or a derivative thereof.

Selected metallic surfaces within the meaning of the present inventionare made from metals such as chromium, niobium, tantalum, vanadium,zirconium, aluminium, cobalt, nickel, stainless steels or alloysthereof. Excluded are metallic titanium and metallic titanium alloysurfaces.

Ceramic surfaces within the meaning of the present invention arepreferably made from a metal oxide, metal carbide, metal nitride, metaloxynitride, metal carbonitride and/or metal oxycarbide. Examples of suchmetal oxides, carbides, nitrides, oxynitrides, carbonitride oroxycarbides are those of chromium, niobium, tantalum, vanadium,zirconium, aluminium, cobalt, nickel, stainless steels or alloysthereof, included also titanium carbide, titanium nitride, titaniumoxynitride, titanium carbonitride and/or titanium oxycarbide.

Implants according to the present invention may be used as prostheses inmedicine, more specifically in orthopaedics, for replacing orstrengthening broken or diseased bones, and in dentistry, for anchoringartificial teeth and for anchoring of bone anchored hearing prosthesis.It has been shown that surfaces modified according to the presentinvention surprisingly enhance the bone bonding strength.

Implants which are used as prostheses in medicine for replacing orstrengthening broken or diseased bones or as artificial teeth are known.These implants must be made of a non-corrosive material and must becompatible with the surrounding tissue without producing immunologicreactions effecting rejection by the body. In the following the terms“surface” or “contact surface” refer to the defined metallic or ceramicimplant surface not yet treated according to the present invention andthe term “modified surface” to said surface treated according to thepresent invention.

It is known that implanting devices in the form of screws, plates,nails, pins, and specially formed parts into the skeletal structure ofhumans and animals as artificial prosthetic is a means for permanentreplacement of missing structural parts or as permanent anchoringdevices. An excellent “osseointegration” is required for thosesituations where the implanted device should remain permanently adheredto the contacting bone surface.

It is known to use selected metals and selected ceramic materials forimplants. When carefully produced, the implant with its surface exhibitsbiocompatibility in the sense that it remains passive for boneregeneration and does not per se induce adverse reactions such asinflammation or soft tissue generation or encapsulation. The interfaceobtained between the implant and the bone tissue normally consists of aprotein layer of about 100 nm to 1 μm thickness preventing the bonetissue from being in direct molecular contact with the implant.

The actual state of the art for endosseous implants is based ondifferent approaches, for example (i) the creation of a suitableroughness of the implant surface giving a mechanical interlockingbetween bone and implant and/or (ii) coating the surface of the implant,e.g. with an artificial hydroxyapatite for improving the healing processand the bone-implant intimate contact.

It is known that a high surface roughness increases the mechanicalstability of the implant in the bone tissue. Mechanical surfacetreatment significantly alters the topography, while the surfacechemistry remains substantially unchanged. The disadvantages of animplant with a high surface roughness are that a purely mechanicalanchoring is very sensible to micromotions which may lead to adeterioration of the mechanical anchorage and that the osseointegrationtime of the implant is relatively long.

Coating the surface of the implant with an artificial hydroxyapatitedecreases the osseointegration time. However, it is very difficult, ifnot impossible, to produce hydroxyapatite coatings with a long termstability on load bearing implants. The interface between the coatingand the implant is often disrupted or the coatings are flaked off.

It has now been found that if the surface of an endosseous implant whichhas a selected metallic or ceramic surface as defined herein is treatedwith at least one organic compound carrying at least one phosphonic acidgroup [—P(O)(OH)₂] or a derivative thereof, as defined herein below,said surface shows a surprisingly improved bone bonding strength and asurprisingly shortened osseointegration time compared to the non treatedsurface and does not have the disadvantages as known for surfaces havinga hydroxyapatite coating.

The present invention is defined in the claims. The present inventionspecifically refers to an endosseous implant to be applied to a human oranimal bone, said implant having a surface made from a selected metal ora selected metal alloy or a ceramic, whereby said metal resp. metalalloy is selected from chromium, niobium, tantalum, vanadium, zirconium,aluminium, cobalt, nickel, stainless steels or an alloy thereof, saidsurface having a smooth or rough texture, characterized in that saidsurface has been treated with at least one pharmaceutically acceptableorganic compound carrying at least one phosphonic acid group or aderivative thereof, which is preferably a pharmaceutically acceptableester or amide or a salt thereof.

The present invention further refers to a process for producing theimplant according to the present invention, which is characterized inthat said surface is treated with at least one pharmaceuticallyacceptable organic compound carrying at least one phosphonic acid groupor a derivative thereof preferably an ester or an amide or a saltthereof.

The metallic surface of the endosseous implant to be treated accordingto the present invention is made from chromium, niobium, tantalum,vanadium, zirconium, aluminium, cobalt, nickel, stainless steels or analloy thereof. Such metals and metal alloys for making implants aredescribed for example in Breme et al., Metals as biomaterials, pp. 1–71(1998), John Wiley & Sons Ltd, Chichester, England; J. B. Park and R. S.Lakes, Biomaterials, An Introduction (1992), 2nd Edition, Plenum Press,New York) pp. 79–115 and 293–354; R. Schmidt, Comportement des matériauxdans les milieux biologiques, Applications en médecine etbiotechnologie, Vol. 7 (1999) pp. 294–343, Presses polytechniques etuniversitaires romandes, Lausanne, Switzerland, the relevant contents ofwhich are incorporated herein by reference.

Alternatively, the surface of the endosseous implant to be treatedaccording to the present invention may be made of a ceramic. Suchceramic surfaces are for example metallic surfaces which have beentreated thermally or chemically or treated with a plasma or anotherappropriate method. Such treatments are known and have been described inthe literature, such as oxide surfaces, carbide surfaces, nitridesurfaces, oxynitride surfaces, carbonitride surfaces or oxycarbidesurfaces, for example those of chromium, niobium, tantalum, vanadium,zirconium, aluminium, cobalt, nickel, stainless steels or alloysthereof. Included are titanium carbide, titanium nitride, titaniumoxynitride, titanium carbonitride and/or titanium oxycarbide. Excludedfrom the present invention are surfaces made from titanium oxide.

Such surfaces and their production is known and is described for examplein H. Bender et al., Surf. Interface Anal. 14 (1989) pp. 337fs.Preferred ceramic surfaces which are made from metal oxides, arealuminium oxide or zirconium oxide or silicon oxide, preferably fromapatites, preferably hydroxyapatite or fluoroapatite, or apatite likematerials, preferably tricalciumphosphate, or brushite type layers suchas are described for example in Breme et al., Metals as biomaterials,pp. 219–264 (1998), ed. J. A. Helsen et al., John Wiley & Sons Ltd,Chichester, England; or J. B. Park and R. S. Lakes, Biomaterials, AnIntroduction (1992), 2nd Edition, Plenum Press, New York, pp. 117–140and 169–183; or R. Schmidt, Comportement des matériaux dans les milieuxbiologiques, Applications en médecine et biotechnologie, Vol. 7 (1999),pp. 306–314, Presses polytechniques et universitaires romandes,Lausanne, Switzerland).

Other ceramic surfaces which may be used within the scope of the presentinvention may be glass like surfaces made for example from silicateglass, or boron silica glass, or bioglass such as described for examplein R. Schmidt, Comportement des matériaux dans les milieux biologiques.Applications en médecine et biotechnologie, Vol. 7 (1999), pp. 306–314,Presses polytechniques et universitaires romandes, Lausanne, Switzerlandas well as in other literature references cited above. the contents ofwhich are incorporated herein by reference.

Preferred organic compounds to be used within the scope of the presentinvention have at least one phosphonic acid group or a derivativethereof, which is preferably an ester or an amide or a salt thereof,resp. preferred implants have a surface which has been treated with atleast one organic compound, or a mixture of such compounds,corresponding to the general formula (I):A-[P(O)(OH)₂]_(P)  (I),or a pharmaceutically acceptable derivative thereof, which is preferablyan ester or an amide or a salt thereof, wherein A means A₁ or A₂, and

-   A₁ is a residue of a linear, branched or cyclic, saturated or    unsaturated, hydrocarbon residue with n carbon atoms, whereby said    residue may be substituted by hydroxyl and/or carboxyl and    optionally further interrupted by one or more oxygen and/or sulphur    and/or nitrogen atoms, carrying p phosphonic acid groups, wherein-   n is a number from 1 to 70, preferably 1 to 40, preferably 1 to 22,    and-   p is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3, 4 or 5, preferably 1,    2, 3 or 4; or-   or A means A₂ and A₂ is a residue of an amino acid or of a sequence    of amino acids resp. of a protein or of a polypeptide, preferably a    residue of the superfamily of Transforming Growth Factor beta    (TGF-β); or a residue of a specific drug molecule, wherein each    residue A₂ carries p phosphonic acid groups, and-   p is 1 to 6, preferably 1, 2, 3 or 4, preferably 1, 2, or 3, when A₂    is a residue of an amino acid or of a sequence of amino acids resp.    of a protein or of a polypeptide; or-   p is 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, and preferably 1,    when A₂ is a residue of a specific drug molecule originally not    bearing any phosphonic group, optionally falling under the    definition given for A₁.

Compounds (i) and (ii) of the general formula (I) are preferred:

-   (i) If A has a meaning of A₁, then: when n is 1 and p is 2: A is    preferably —CH₂—; or when n is 1: p is preferably 3 or 4, preferably    3; or when n is 2 to 10: p is preferably 2, provided each phosphonic    acid group or phosphonic acid ester group or phosphonic acid amide    group is bound to a different carbon atom within the same molecule;    or when n is 2 to 10: p is preferably 3, 4, 5 or 6, preferably 3, 4    or 5, preferably 3 or 4; or when n is 11 to 70: p is preferably 2,    3, 4, 5 or 6, preferably 2, 3, 4 or 5, preferably 2, 3 or 4.-   (ii) If A has the meaning of A₂, then: p is preferably 1 or 3–6,    preferably 1, for the case that A₂ is a residue of a specific drug    molecule originally not bearing any phosphonic group, optionally    falling under the definition given for A₁.

It is assumed that the phosphonate compounds as specified herein,especially as acids or salts, form a covalent bond with the surface ofthe implant thereby improving the osseo-integration properties of saidsurface to a remarkable and unexpected extent. The present inventionhowever is not bound to this explanation.

A₁ preferably is a saturated hydrocarbon residue of the formula—(C_(n)H_(2n+2−p))—, wherein n means 1 to 70, preferably 1 to 40,preferably 1 to 22. Preferred is the free acid or the salt form of thecompound of formula (I), preferably where the pharmaceuticallyacceptable salt is an alkali salt, preferably of sodium or potassiumsalt.

Examples of compounds of formula (I) wherein A₁ is a residue of asaturated hydrocarbon [e.g. an alkyl chain with 1 to 70 carbon atoms(C₁–C₇₀-Alkyl)] are monophosphonic acids such as methanephosphonic acid,ethanephosphonic acid, propane-phosphonic acid or polyphosphonic acidssuch as methylenediphosphonic acid, ethane-1,2-diphosphonic acid,propane-1,3-diphosphonic acid, ethane-1,1,2-triphosphonic acid,propane-1,1,3-triphosphonic acid, butane-1,1,4-triphosphonic acid,pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic acid,heptane-1,4,4,7-tetraphosphonic acid, propane-1,1,3,3-tetraphosphonicacid, or nonane-1,5,5,9-tetraphosphonic acid.

Examples of compounds of formula (I) wherein A₁ is a residue of anunsaturated hydrocarbon are unsaturated monophosphonic acids andpolyphosphonic acids such as those given in H.

Fleisch, Bisphosphonates in bone disease, from the laboratory to thepatient 2000, 4rd edition, The Parthenon Publishing Group, p.31–33,which compounds are incorporated herein by reference.

If the pharmaceutically acceptable ester is used, the isopropylphosphonate or ethyl phosphonate esters, preferably of the acids givenin the two previous chapters, are preferred. Further examples of suchesters are: tetra isopropyl methylenediphosphonate, hexaethylethane-1,1,2-triphosphonate, hexaisopropyl butane-1,1,4-triphosphonate,hexaisopropyl pentane-1,1,5-triphosphonate, hexaisopropylpentane-2,2,5-triphosphonate, hexaisopropyl hexane-2,2,6-triphosphonate,octaisopropyl propane-1,1,3,3-tetraphosphonate, octaisopropylheptane-1,4,4,7-tetraphosphonate, octaisopropylnonane-1,5,5,9-tetraphosphonate.

Examples of compounds of formula (I) wherein A₂ is a residue of aprotein resp. polypeptide are compounds in the form of a TransformingGrowth Factor beta (TGF-β) in which are included the all members of thesuperfamily of growth factors and particularly the TGF-β1, TGF-β2,TGF-β3, TGF-β4, and TGF-β5 as described for example in A. B. Roberts, M.B. Sporn, Handbook of Experimental Pharmacology, 95 (1990) pp. 419–472or D. M. Kingsley, Genes and Development 8 (1994) p. 133–146, andreferences therein, where the peptide chain has been modified to containan alkylphosphonic acid group or a derivative thereof preferably anester or an amide or a salt thereof. In this sense the compound offormula (I) represents a Transforming Growth Factor beta (TGF-β) asdefined by the members of the superfamily of growth factors, preferablythe TGF-β1, TGF-β2, TGF-β3, TGF-β4, and TGF-β5, wherein each time thepeptide chain has been modified to contain at least one alkylphosphonicacid group or a derivative thereof preferably an ester or an amide or asalt thereof.

Examples of compounds of formula (I) wherein A is a residue of a BoneMorphogenic Protein (BMP) (being a subfamily to the TGF family) arecompounds e.g., the BMP-2 (BMP-2a), BMP-3, BMP-4 (BMP-2b), BMP-5, BMP-6,BMP-7 (OP-1), BMP-8 (OP-2), BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, asfound for example in J. M. Wozney et. al., Science 242 (1988) 1528–1534;A. J. Celeste et al., Proc. Natl. Acad. Sci. USA 87 (1990) 9843–9847; E.Özkaynak et al., J. Biol. Chem. 267 (1992) 25220–25227; Takao et al.,Biochem. Biophys. Res. Com. 219 (1996) 656–662; WO 93/00432; WO94/26893; WO 94/26892; WO 95/16035 and references therein, where thepeptide chain has been modified to contain an alkylphosphonic acid groupor a derivative thereof preferably an ester or an amide or a saltthereof. These compounds are incorporated herein by reference. In thissense the compound of formula (I) represents a Bone Morphogenic Protein(BMP), preferably the BMP-2 (BMP-2a), BMP-3, BMP-4 (BMP-2b), BMP-5,BMP-6, BMP-7 (OP-1), BMP-8 (OP-2), BMP-9, BMP-10, BMP-11, BMP-12,BMP-13, wherein the peptide chain has been modified to contain at leastone alkylphosphonic acid group or a derivative thereof preferably anester or an amide or a salt thereof.

Examples of compounds of formula (I) wherein A₂ is a residue of an aminoacid are 2-amino-4,4-bis-(diethoxy-phosphoryl)-butyric acid as describedfor example in O. Fabulet et al., Phosphorus, Sulphur Silicon andRelated Elements, 101, 225–234 (1995);2-amino-5-(diethoxy-phosphoryl)-pentanoic acid as described for examplein I. G. Andronova et al., Russ. J. Gen. Chem. 66, 1068–1071 (1996);2-amino-4-phosphonobutyric acid as described for example in X. Y. Jiaoet al., Synth. Commun. 22, 1179–1186 (1992) and references therein.Further examples are all the principal twenty amino acids as describedfor example in L. Stryer, Biochemistry, 3rd edition (1988), pp. 17–22,where the amino acid is modified in an analogous way with analkylphosphonic acid group, preferably wherein the compound of formula(I) is one of the principal twenty amino acids, preferably arginine,glycine, aspartic acid, alanine, valine, proline, serine, threonine,cysteine or lysine, wherein the amino acid has been modified to containat least one alkylphosphonic acid group or a derivative thereofpreferably an ester or an amide or a salt thereof. These compounds areincorporated herein by reference.

Examples of compounds of formula (I) wherein A₂ is a residue of apeptide comprise but are not limited to RGD-containing peptides,RGDS-peptides, GRGDS-peptides, RGDV-peptides, RGDE-peptides, and/orRGDT-peptides. Such peptides are described for example in Y. Hirano, J.Biomed. Materials Res., 25 (1991), pp. 1523–1534 or in WO 98/52619 andreferences therein. Included within the scope of the present inventionare also similar peptides known to have specific biological activitiessuch as cell attachment or cell attachment prevention, and which areprepared in analogy with the peptides as mentioned above. In this sensethe compound of formula (I) is a RGD-containing peptide, preferably aRGDS-peptide, a GRGDS-peptide, a RGDV-peptide, a RGDE-peptide, and/or aRGDT-peptide, which has been modified to contain at least onealkylphosphonic acid group or a derivative thereof preferably an esteror an amide or a salt thereof.

Examples of compounds of formula (I) wherein A₂ is a residue of aspecific drug molecule are 1-hydroxy-3-(1-pyrrolidinyl)-propylidenediphosphonic acid, or cycloheptylamino-methylene diphosphonic acid, or1-hydroxy-2-imidazo-(1,2-a)-pyridin-3-yl-ethylidene diphosphonic acid or1-hydroxy-2-(3-pyridinyl)-ethylidene diphosphonic acid or(4-chlorophenyl)thio-methylene diphosphonic acid or1-hydroxy-2-(1H-imidazole-1-yl)ethylidene diphosphonic acid and relatedcompounds as described for example in H. Fleisch, Bisphosphonates inbone disease, from the laboratory to the patient 2000, 4rd edition, TheParthenon Publishing Group, pp. 31–33, and references therein. Suchcompounds are included herein by reference.

Preferred compounds of formula (I) are those containing a residue A₂ asdefined above, preferably a residue of an amino acid or of a sequence ofamino acids resp. of a protein or of a polypeptide, preferably a residueof the superfamily of Transforming Growth Factor beta (TGF-β),preferably a Bone Morphogenic Protein (BMP).

The following steps are recommended to be taken for producing theimplant according to the present invention, i.e. for treating thesurface of the implant with at least one compound of formula (I) or amixture of these compounds. The implant is first cleaned in a cleaningbath for removing unwanted molecules resp. impurities from the surface.Preferably the implant is first treated with a degreasing agent, forexample an organic solvent such as alcohol, chloroform, and anotherorganic solvent and/or an inorganic detergent such as an aqueousalkaline solution based on sodium hydroxide or potassium hydroxide.Subsequently, the implant is carefully rinsed in pure water, preferablyin distilled ultra-pure water, having preferably a conductivityresistance of at least 15 Mohm*cm. After cleaning and rinsing, theimplant is dried with flowing nitrogen gas or flowing dry or hot air andstored under controlled conditions. Alternatively after degreasing theimplant can be further treated in a glow-discharge plasma for cleaningthe surface. The clean surface of the implant is then treated with atleast one compound of formula (I) or an ester or a salt thereof, i.e.with at least one such compound or a mixture of such compounds. Thecompound or the mixture of said compounds is brought onto the surface ofthe implant by any suitable means, like brushing, spraying, dipping or,evaporation, including glow-discharge plasma assisted vapour deposition.The phosphonic acid compound or the ester or the salt thereof ispreferably dissolved in a polar solvent, so that a solution with aconcentration of from about 1.0×10⁻⁵ mol/10 ml to 5×10² mol/10 ml,preferably from about 5×10⁻⁴ mol/10 ml to 2.0×10⁻² mol/10 ml withreference to the weight of the solvent is obtained. Preferably theconcentration is such that a partial or full (1% to 100%, preferably 50%to 100% of a) monomolecular layer is formed on the implant surface. Thepreferred solvent is pure distilled water. The implant is left incontact with the solution for a sufficiently long time, preferably for afew minutes up to a few hours. After that the implant is carefullyrinsed with pure water and packed with a plastic or metallic cleanpackaging material preferably into an air tight packaging whichpreferably is evacuated or filled with an inert gas such as nitrogen oran inert liquid such as pure water as defined herein above. Said purewater may contain inorganic salts, preferably alkali salts, such asalkali chlorides, sulphates, phosphates, phosphonates, preferably thesodium and/or potassium salts, and/or compounds of the formula (I) or anester or a salt thereof, which is preferably in a concentration of fromabout 1.0×10⁻⁵ mol/10 ml to 5×10⁻² mol/10 ml, preferably from about5×10⁻⁴ mol/10 ml to 2.0×10⁻² mol/10 ml of solvent, which preferably isdistilled water.

Analytical investigations, e.g. X-ray Photoelectron Spectros-copyanalysis (XPS) or NMR, have shown that on contacting the phosphonic acidcompound of formula (I) with the surface of the implant, immediateadsorption takes place. A strong bond is formed between the surface andthe phosphonic acid compound so that a chemical surface modification isobtained. Several different polyphosphonic acids, salts, esters andamides as mentioned herein above were synthesized. Dental implantsproduced with these compounds according to the present invention haveshown excellent results.

Implants according to the present invention may be in the form ofscrews, plates, nails, pins, and specially formed parts and may be usedas prostheses in medicine, more specifically in orthopaedics, forreplacing or strengthening broken or diseased bones, and in dentistry,for anchoring artificial teeth and for anchoring of bone anchoredhearing prosthesis into the skeletal structure of humans and animals.The surface area of the implant which is to be bound to the body tissueresp. bones, may have a smooth or rough surface texture. Such surfacetextures are known and can be obtained for example by treating thesurface mechanically and/or with acids and/or electrolytically and/orwith a glow-discharge plasma and/or plasma spraying and/or or by electromachining. Such materials and processes have been described in differentpublications, for example in B.-O. Aronsson et al., J. Biomed. Mater.Res. 35 (1997), pp. 49f., the contents of which are incorporated hereinby reference.

The compounds according to the general formula (I), wherein p is 3 to 6,preferably 3 or 4, and n is 4 to 70, preferably 4 to 40, preferably 4 to22, the salts or esters or amides thereof are new. Examples of suchcompounds are butane-1,1,4-triphosphonic acid,pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic acid,heptane-1,4,4,7-tetraphosphonic acid, or nonane-1,5,5,9-tetraphosphonicacid.

The compounds hexaisopropyl butane-1,1,4-triphosphonate andoctaisopropyl heptane-1,4,4,7-tetraphosphonate, resp. a mixture of thesecompounds, are obtained in that an alkalimetal, preferably sodium, tetralower alkyl methylenediphosphonate, preferably tetraisopropylmethylenediphosphonate, is reacting with at least a stoichiometricamount of a dihalomethane, preferably dibromomethane, in the presence ofan organic solvent having no active hydrogen atoms, preferably dryhexane or benzene or toluene.

The reaction is preferably carried out at a temperature within the rangeof 30° C. to 125° C., preferably 40° C. to 110° C., until the reactionis completed, which generally is within a time period of 10 to 48 hours,preferably 18 to 36 hours.

To the reaction product is then added the purified product oftriisopropylphosphite that has been reacted withdiisopropyl-3-bromopropane. The obtained mixture of compounds can thenbe separated in a conventional manner, for example by columnchromatography.

In an analogous way, by reacting 1,4-dibromobutane in excess molar ratioin the range 1:6 to 1:0.5 with triisopropylphosphite, surprisingly thenew compounds hexaisopropyl pentane-1,1,5-triphosphonate andoctaisopropyl nonane-1,5,5,9-tetraphosphonate are produced. Further, inan analogous way the hexaisopropyl pentane-2,2,5-triphosphonate andhexaisopropyl hexane-2,2,6-triphosphonate were obtained by reactingequal parts of tetraisopropylethane-1,1-diphosphonate withdiisopropyl-3-bromopropylphosphonate.

The process is further characterised by that these products arehydrolysed to produce the analogous acids by refluxing them in molarexcess of HCl for a time comprised within 1 to 12 hours, preferably 1 to6 hours. The compounds are then preferably dried under vacuum over P₂O₅.

The following Examples illustrate but do not limit the presentinvention.

EXAMPLE 1 Synthesis of Alkane Polyphosphonic Acids

Methylenediphosphonic acid was synthesized according to U.S. Pat. No.3,400,176 and B. A. Arbusov, Pure Appl. Chem. 9 (1967), pp. 307–353 andreferences therein. The compound was characterized by NMR (¹H, ³¹P, ¹³C)mass spectroscopic elemental analysis and by its melting point. Allthese data are in accordance with the literature O. T. Quimby et al.,Metalated methylendiphosphonate esters, preparation, characterizationand synthetic applications, J. of Organomet. Chem. 13, 199–207 (1968).

Propane-1,1,3,3-tetraphosphonic acid was synthesized from tetraisopropylmethylenediphosphonate. The tetraphosphonic acidic solution wasconcentrated under vacuum, dried over P₂O₅ under vacuum. The ¹H, ³¹P and¹³C NMR results (D₂O) are in accordance with the given literature data.

In an analogous manner propane-1,3-diphosphonic acid,ethane-1,1,2-triphosphonic acid, butane-1,1,4-triphosphonic acid,pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic acid orheptane-1,4,4,7-tetraphosphonic acid, are synthesized.

EXAMPLE 2

A) A dental implant made from titanium in the form of a screw, having adiameter of 4 mm and a length of 10 mm, is produced in a conventionalmanner. The surface to be implanted into the body is provided with asurface roughness according to EP 0 388 575 by sandblasting the surfaceusing an average grain size of 0.25–0.5 mm, followed by a treatment witha mixture of an aqueous acidic mixture containing a mixture ofhydrochloric acid/sulfuric acid/water in a ratio of 2:1:1, at atemperature of about 80° C. for about 5 minutes so that a rough surfaceof the implant is obtained which is about 3.6 times larger compared tothe polished surface, as measured with the voltametric method in aqueouselectrolyte with 0.15M NaCl. The surface of the implant is thenchemically treated with a nitrogen plasma to yield a titanium nitridesurface as described in B.-O. Aronsson et al., J. Biomed. Mater. Res. 35(1997), pp. 49f. The treated implant, resp. surface, is sonicated inbidistilled water during 15 minutes at 30° C., washed with pure waterfollowed by sonication in water (three times) for 10 minutes and thenrinsed with pure hexane and dried under vacuum (10 mm Hg, roomtemperature).

B) The implant as produced in chapter A) above is then put into anaqueous solution of (i) methylenediphosphonic acid [1,5×10⁻³ mol per 10ml of distilled water], (ii) ethane-1,1,2-triphosphonic acid [6.2×10⁻⁴mol/10 ml, in distilled water], (iii) pentane-1,1,5-triphosphonic acid[1.2×10⁻⁴ mol/10 ml, in distilled water], (iv)pentane-1,1,5-triphosphonic acid potassium salt [1.2×10⁻⁴ mol/10 ml, indistilled water] and left there at room temperature for 15 minutes. Theimplant is then rinsed with pure water.

The implant prepared according to the preparations B(i), B(ii), B(iii)and B(iv) are implanted into the upper jaw of a mini pig. Theosseointegration is measured as the torque needed to unfasten theimplant from the jaw where it had osseointegrated. Comparative testresults are given for the untreated implant. The results are given inTable 1. Analogous results are obtained for further phosphonic acidsgiven herein above. Analysis with XPS and ToF-SIMS indicated that amolecular (mono) layer was formed on the implant surface as well as onthe titanium nitride surface, and that the roughness of the surface didnot seem to influence this behaviour.

TABLE 1 Torque* after 2 torque* after 3 torque* after 4 Preparationweeks (Ncm) weeks (Ncm) weeks (Ncm) B(i) 31 72 130 B(ii) 30 80 125B(iii) 32 79 132 B(iv) 29 83 124 Comparative 20 60 100 Test *the torqueis given in Ncm as an average value from three measurements for eachtest.

The results illustrate the improved osseointegration of the implantsaccording to the present invention compared to the non treated implants.

EXAMPLE 3

Example 2 is repeated with the difference that the original titaniumsurface of the implant is treated with methane in an argon glowdischarge plasma so that a surface of titanium carbide is obtained. Thetreatment is performed as described in B.-O. Aronsson et al., J. Biomed.Mater. Res. 35 (1997), pp. 49f. Analogous test results are obtainedanalogous to those given in Table 1.

EXAMPLE 4

Example 2 is repeated with the difference that the implant is made ofzirconium, having a zirconium oxide surface, and that the compoundaccording to formula (I) is ethane-1,1,3-triphosphonic acid which hasbeen modified by linking the amine terminus of a Glycine molecule to oneof the phosphonate groups. Analogous test results are obtained as givenin Table 1.

EXAMPLE 5

Examples 2 and 3 are repeated with the difference that the compoundaccording to formula (I) is the ethane-1,1,3-triphosphonic acid which ismodified by linking the amine terminus of a GRGDS cell bindingpolypeptide to one of the phosphonate groups. Analogous results areobtained as given in Table 1.

EXAMPLE 6

Examples 2 and 3 are repeated with a the difference that the compoundaccording to formula (I) is ethane-1,1,3-triphosphonic acid which ismodified by linking the amine terminus (Methionine) of a human BoneMorphogenic Protein type 2 (BMP-2) to one of the phosphonate groups,which gives analogous test results as given in Table 1.

1. An endosseous implant suitable for application to a human or animalbone, said implant having a surface made from a selected metal or aselected metal alloy or a ceramic, whereby said metal resp. metal alloyis selected from chromium, niobium, tantalum, vanadium, zirconium,aluminium, cobalt, nickel, stainless steels or an alloy thereof, saidsurface having a smooth or rough texture, wherein said surface has alayer formed thereon of at least one pharmaceutically acceptable organiccompound carrying at least one phosphonic acid group or a derivativethereof, which is a pharmaceutically acceptable ester, amide or saltthereof, corresponding to the formula (I):A-[P(O)(OH)₂]_(p)  (I), wherein A means A₁ or A₂, and A₁ is a residue ofa linear, branched or cyclic, saturated or unsaturated, hydrocarbonresidue with n carbon atoms, whereby said residue may be substituted bycarboxyl and optionally further interrupted by one or more oxygen and/orsulphur and/or nitrogen atoms, carrying p phosphonic acid groups,wherein n is a number from 1 to 70, and p is 1, 2, 3, 4, 5 or 6, or Ameans A₂ and A₂ is a residue of an amino acid or of a sequence of aminoacids respectively of a protein or of a polypeptide; or a residue of aspecific drug molecule, wherein each residue A₂ carries p phosphonicacid groups, and p is 1 to 6, when A₂ is a residue of an amino acid, ofa sequence of amino acids, of a protein or of a polypeptide; or p is 1,2, 3, 4, 5 or 6, when A₂ is a residue of a specific drug moleculeoriginally not bearing any phosphonic group, optionally falling underthe definition given for A₁.
 2. The implant according to claim 1,wherein the surface of the implant is made of a ceramic selected fromoxide surfaces, carbide surfaces, nitride surfaces, oxynitride surfaces,carbonitride surfaces and oxycarbide surfaces of chromium, niobium,tantalum, vanadium, zirconium, aluminium, cobalt, nickel, stainlesssteels or alloys thereof.
 3. The implant according to claim 1, whereinthe surface of the implant is made of titanium carbide, titaniumnitride, titanium oxynitride, titanium carbonitride and/or titaniumoxycarbide.
 4. The implant according to claim 1, wherein the surface ofthe implant is made from a metal oxide or an apatite material.
 5. Theimplant according to claim 1, wherein the surface of the implant is madeof a glass material.
 6. The implant according to claim 1, wherein n inresidue A₁ is a number from 1 to 40, and p in formula (1) is 1, 2, 3, 4or 5; or p is 1, 2, 3 or 4, when A₂ is a residue of an amino acid or ofa sequence of amino acids, of a protein or of a polypeptide; or p is 1,2 or 3, when A₂ is a residue of a specific drug molecule originally notbearing any phosphonic group, optionally falling under the definitiongiven for A₁.
 7. The implant according to claim 1, wherein A has ameaning of A₁, and: when n is 1 and p is 2: A is —CH₂—; or when n is 1:p is 3 or 4; or when n is 2 to 10: p is 2, provided each phosphonic acidgroup or phosphonic acid ester group is bound to a different carbon atomwithin the same molecule; or when n is 2 to 10: p is 3, 4, 5 or 6; orwhen n is 11 to 70: p is 2, 3, 4, 5 or
 6. 8. The implant according toclaim 1, wherein A has a meaning of A₂, and: p is 1 or 3–6, for the casethat A₂ is a residue of a specific drug molecule originally not bearingany phosphonic group, optionally falling under the definition given forA₁.
 9. The implant according to claim 1, wherein A₁ is a saturatedhydrocarbon residue of the formula —(C_(n)H_(2n+2-p))—, wherein n means1 to
 70. 10. The implant according to claim 1, wherein the compound offormula (I) is an alkali salt.
 11. The implant according to claim 1,wherein the compound of formula (I) is selected from a saturatedmonophosphonic acid, a saturated polyphosphonic acid, an unsaturatedmonophosphonic acid and an unsaturated polyphosphonic acid.
 12. Theimplant according to claim 1, wherein the pharmaceutically acceptableester is an isopropyl phosphonate or ethyl phosphonate ester.
 13. Theimplant according to claim 12, wherein the ester is selected from tetraisopropyl methylenediphosphonate, hexaethyl ethane-1,1,2-triphosphonate,hexaisopropyl butane-1,1,4-triphosphonate, hexaisopropylpentane-1,1,5-triphosphonate, hexasopropyl pentane-2,2,5-triphosphonate,hexaisopropyl hexane-2,2,6-triphosphonate, octaisopropylpropane-1,1,3,3-tetraphosphonate, octaisopropylheptane-1,4,4,7-tetraphosphonate, and octaisopropylnonane-1,5,5,9-tetraphosphonate.
 14. The implant according to claim 1,wherein the compound of formula (I) represents a Transforming GrowthFactor beta (TGF-β) as defined by members of the superfamily of growthfactors, selected from TGF-β1, TGF-β2, TGF-β3, TGF-β4, and TGF-β5,wherein in each member the peptide chain has been modified to contain atleast one alkylphosphonic acid group or a derivative thereof.
 15. Theimplant according to claim 1, wherein the compound of formula (I)represents a Bone Morphogenic Protein (BMP), selected from BMP-2(BMP-2a), BMP-3, BMP-4 (BMP-2b), BMP-5, BMP-6, BMP-7 (OP-1), BMP-8(OP-2), BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, wherein the peptide chainhas been modified to contain at least one alkylphosphonic acid group ora derivative thereof.
 16. The implant according to claim 1, wherein thecompound of formula (I) is selected from2-amino-4,4-bis-(diethoxy-phosphoryl)-butyric acid,2-amino-5-(diethoxy-phosphoryl)-pentanoic acid and/or2-amino-4-phosphonobutyric acid.
 17. The implant according to claim 1,wherein the compound of formula (I) is selected from one of theprincipal twenty amino acids, wherein the amino acid has been modifiedto contain at least one alkylphosphonic acid group or a derivativethereof.
 18. The implant according to claim 1, wherein the compound offormula (I) is a RGD-containing peptide, selected from a RGDS-peptide, aGRGDS-peptide, a RGDV-peptide, a RGDE-peptide, and/or a RGDT-peptide,which has been modified to contain at least one alkylphosphonic acidgroup or a derivative thereof.
 19. The implant according to claim 1,wherein the compound of formula (I) is selected from1-hydroxy-3-(1-pyrrolidinyl)-propylidene diphosphonic acid,cycloheptylamino-methylene diphosphonic acid,1-hydroxy-2-imidazo-(1,2-a)-pyridin-3-yl-ethylidene diphosphonic acid,1-hydroxy-2-(3-pyridinyl)-ethylidene diphosphonic acid,(4-chlorophenyl)thio-methylene diphosphonic acid and1-hydroxy-2-(1H-imidazole-1-yl)ethylidene diphosphonic.
 20. The implantaccording to claim 1 in the form of a screw, plate, nail, or pin.
 21. Aprocess for producing the implant according to claim 1, which comprisestreating said surface with at least one pharmaceutically acceptableorganic compound of formula (I) or a salt or ester or an amide thereof,to form said layer thereon.
 22. An air tight plastic or metallicpackaging material which optionally is evacuated or filled with an inertgas or an inert liquid containing an implant according to claim
 20. 23.A packaging material according to claim 22, wherein said packagingmaterial is filled with pure water containing an inorganic salt and/or acompound of formula (I) or a salt or ester thereof.
 24. A packagingmaterial according to claim 23, wherein the concentration of inorganicsalt and/or a compound of formula (I) or a salt or ester thereof is fromabout 1.0×10⁻⁵ mol/10 ml to 5×10⁻² mol/10 ml of the water.
 25. Acompound of formula (I) or salt or ester thereof according to claim 1,wherein p is 3 to 6, and n is 4 to
 70. 26. The compound according toclaim 25, selected from butane-1,1,4-triphosphonic acid,pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic acid,heptane-1,4,4,7-tetraphosphonic acid, nonane-1,5,5,9-tetraphosphonicacid, a salt thereof, an ester thereof and an amide thereof.